Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

optic nerve tolerates has individual variability. This explains why an IOP between 10 and 21 mmHg (considered normal) can, in some cases, cause damage. The examination of the patient should include slit lamp observation, tonometry, optic disk morphology study, and iris-corneal angle evaluation. Ophthalmoscopy evaluates the relationship between optic excavation and the optic disk diameter or cup/ disk ratio. Signs of pathology are values of about 0.5, and a difference of more than 0.2 between the two eye ratios. Perimetry evaluates visual field alterations; there are typical alterations in the glaucomatous patient. Gonioscopy allows direct observation of the anterior chamber angle and can show shallow chambers and angle closure.

Prevention is fundamental in this pathology, as glaucoma is a silent disease with progressive functional damage leading to blindness. The therapeutic management of glaucoma includes systemic or local use of drugs. However, when these do not permit adequate control of disease, parasurgical and surgical treatment is indicated. Medical treatment of glaucoma is aimed at intervening in aqueous humour dynamics on the following systems:43,44

●secretion of aqueous humour; beta-blockers; inhibitors of anhydrase carbonate; alpha2-antagonists;

●trabecular drainage; miotic agents; epinephrine;

●venous episcleral perfusion/ciliary body perfusion; alpha-2-agonist with alpha- 1-agonistic properties.45-48.

Medical treatment must be used constantly, and in this manner the majority of patients maintain IOP under control. Frequently an association of drugs administered once or twice daily is necessary.49,50 The use of laser techniques began in 1956 when Meyer-Schwickerath created an iridotomy without surgical incision using xenon arc photocoagulation.51 Later the pulsed ruby laser,52,53 followed by the argon laser,54 was used with less damage inflicted on the lens and cornea. Today argon laser iridotomy and neodymium:yttrium-aluminium-garnet (Nd:YAG) laser iridotomy have replaced surgical iridectomy as the primary treatment for angle-closure glaucoma.55 Laser iridotomy has advantages over surgical methods and does not have the risks of intraocular surgery. The primary indication is angle-closure glaucoma due to primary or secondary (iris capture of an intraocular lens or pupillary seclusion in iridocyclitis) pupillary block. Indications for laser peripheral iristomy are also acute, intermittent, and chronic pupillary block or in the treatment of one eye in a patient with angle-closure glaucoma in the other. In patients with narrow angles and after an attack of malignant glaucoma in one eye, prophylactic laser iristomy in the other eye may avert a surgical irisectomy or a trabeculectomy. Another important laser technique is laser trabeculoplasty, which is used to control elevated intraocular pressure in those patients with open-angle glaucoma for whom medical therapy has failed to bring about control. It is also useful in some secondary open-angle glaucoma such as pseudoexfoliative and pigmentary glaucoma.56 It can also be used after filtration surgery where intraocular pressure is still high.

Many studies have been carried out regarding the indications for surgical management of the glaucomatous patient. Surgical treatment is usually indicated when

medical and laser treatment is not sufficient to prevent the progression of disease. Surgery in primary glaucoma is essentially aimed at preventing and “correcting” the state of ocular hypertension in order to limit the progression of irreversible damage to the optic nerve, visual field, and therefore visual function. In the literature there are two concepts on which surgery is based: to modify the anatomic structures of the natural drainage systems at various levels, and to restore the natural paths of drainage. The majority of techniques consist of creating a bypass between the posterior and anterior chamber and the subconjunctival space; that is, creating an artificial drainage system. These can be divided into 1) a bypass between the posterior and anterior chamber (sector iridectomy or peripheral iridectomy); 2) a bypass between the anterior chamber and subconjunctival space at times protected by a scleral flap (filtrating tecniques such as scleral-iridectomy of Lagrange, scleral trephination according to Elliot, iridoenclesis, thermosclerostomy according to Schede) protected filtration such as trabeculectomy, or non filtration techniques such as viscocanalastomy and deep sclerectomy. In patients who techniques to enhance outflow are not possible or have not been successful, operations to decrease aqueous production by destroying portions of the ciliary body can be carried out. These cylio-destructive procedures are used on eyes with neovascular, inflammatory, or aphasic glaucoma. They are also useful in providing comfort in patients with severe vision loss due to glaucoma. Cyclodiathermy was first introduced in 1933.57 Bietti described the use of dry ice for cyclocryotherapy in 1950.58 Today cyclocryotherapy with nitrous oxide gas cooling is used. Lasers are also used to cause ciliary body damage and a decrease in aqueous production. Three principal routes of laser energy administration to the ciliary body have been employed: transpupillary cyclophotocoagulation, endophotocoagulation, and transscleral cyclophotocoagulation. This latter method is the most widely adopted. Noncontact Nd:YAG laser energy is administered via a slit lamp delivery system, with or without a contact lens.

Age-related macular degeneration (AMD) has always been considered a pathology of the elderly. About 30 percent of adults aged 75 or older present some signs of maculopathy; 6-8 percent of these individuals have advanced stages of disease with severe visual loss.59-61 At present it seems to involve younger patients (45-50 years old). Research suggests that AMD is a very complex disease, caused by a combination of multiple genetic and environmental factors. There seems to be strong evidence for the heredity of AMD based on familiar aggregation studies, twin studies, and segregation analysis.

Choroidal neovascularization can represent the initial phase of an eventual choroidal scar.62 This initial stage is called the exudative phase. The later stage is the scar. The increased permeability of neovessels shown with indocyanine green staining and with fluorangiography is defined as leakage. During the neovascularization stage, endothelial growth factor (EGF) is present. The scars are frequently circular; they are called “disciform.” In choroidal neovascular membranes (CNVM), as in all hypo-oxygenation disorders, there is tissue damage or loss followed by tissue repair processes. The cause of tissue destruction in AMD is probably due to apoptosis or programmed cell death. Trauma, laser treatment, and angioid streaks share a common factor, a defect of the retinal pigment epithelium (RPE) and/or of the choriocap-

illaris. The localized relative hypoxia increases the hydrophobic proprieties of Bruch’s membrane, which could play an important role in the physiopathology.

In the United States the prevalence of neovascular AMD in the population over 40 years of age is 1.47 percent. CNVM and the majority of correlated diseases are not associated with higher mortality. Smoking seems to increase the progression of AMD by 350 percent. It is well established that smoking also dramatically increases the incidence of cancer and cardiovascular death. The main symptom of CNVM is loss of central vision, but peripheral vision seems to be preserved unless complications follow surgical management.

The prevalence of AMD increases with age; it is common after age 60, and even more so after 70. The frequency of AMD is 90 percent in Caucasian males over 80 years of age and is 16.39 percent in Caucasian females over 80. In males ocular trauma leading to CNVM is more frequent than in females, whereas AMD is more frequent in females. In the past the aging of the retinal epithelial pigment (REP) cells was considered the pathogenetic mechanism responsible for the disease. However, at present, increasing earlier manifestations of disease have led to a consideration of other factors. An important pathogenetic factor is an altered immune system involved in the elimination of epithelial pigment cells which degenerate and encounter cellular death. The REP cells are terminal differentiated cells similar to cells of the cornea, and do not divide. Therefore, from 20 to 90 years of age there is a progressive loss of retinal cells. Near the fovea there is less cellular loss. There is, however, aging of the pigmented epithelium adjacent to the paramacular drusen. In vitro studies show an increase of the B-glactosidosis enzyme precursor to AMD and also of the factor involved in cellular reproduction. In vivo it is difficult to demonstrate the presence of B-galactosidosis. What happens to the cells that encounter apoptosis? There are certainly changes at the cellular level; an increased sensitivity to calcium, binding of the cellular membrane, DNA fragmentation, appearance of the glycoprotein rich in istidine which determines the clearance of apoptotic cells. The systems which eliminate apoptotic cells are humoral and cellular. The former are based on the activation of the complement pathway and that of the C-reactive protein. The latter are based on dendritic cell morphology which, in studies on mice, are localized under the REP to regulate and control inflammation. Dendritic cells function as scavengers for silent elimination of dead epithelial pigment cells. This function at choroidal level is most probably carried out by macrophages which do not activate the complement. A similar mechanism of cellular regulation for the elimination of dead cells has been observed in bone marrow in humans through the production of complement factors.59-62

What occurs when there is an increased vulnerability to AMD? Most probably the complement factors go out of control, leading to cellular necrosis rather than apoptosis, thus generating angiogenesis. Presumably the normal scavenger function does not determine disease. Altered scavenger regulation due to genetic vulnerability can lead to dry AMD. When there is little complement activation, an accumulation of necrotic cells, and an increase of apoptotic cells, geographic atrophy results. Wet AMD arises when complement factors are activated and are out of control and there is activation of vascular endothelial growth factor (VEGF). AMD is being studied

at the genetic level in order to allow primary prevention in the future; but there is high expressivity of the disease, and further research is warranted. At present secondary prevention is possible by trying to intervene in environmental risk factors and by administering appropriate treatment where the disease is already present.

Careful patient follow-up is essential. This is carried out by examining the ocular fundus of patients and by using instrument techniques such as ocular computerized tomography (OCT), electroretinogram (ERG), visual field examination, fluorangiography (FAG), and indocyanine green angiography (ICG). AMD can have a profound impact on quality of life and independence. Due to the loss of central vision, afflicted individuals may be unable to read, write, or drive. 62 percent of patients with AMD lose three lines of visual acuity in one year.

The management of AMD is limited. The unique proven treatment for the dry form of AMD is antioxidant/mineral supplementation, which slows AMD progression by 25 percent over five years. The approved treatment options for exudative AMD based on clinical trials are laser photocoagulation, photodynamic therapy, and anti-angiogenic agent injection. The major limitation of laser photocoagulation is the damage to the neurosensory retina that is associated with a sudden decrease in visual acuity. Photodynamic therapy is a nonthermal process based on the targeted photoactivation of an intravenously administrated photosensitive drug. The activated dye results in the creation of oxygen intermediates and free radicals affecting the exposed endothelial cells.63

The era of pharmacological treatment of CNV in AMD has just began. Triamciolone acetonate is widely used. The optamer Na-pegaptanib agonist VEGF is used as intravitreal injections. The effects of ranibizumab and bevacizumab are being studied. A cortisone acetate is also being studied which inhibits endothelial cell migration and also reduces the release of VEGF. In contrast to triamcinolone, it has no effect on the lens or intraocular pressure.

Diabetic retinopathy is the most important cause of low vision and blindness in patients of working age in the United States and Europe.

The prevalence of diabetes in Europe is estimated at 2.5 percent of the entire population, and of these patients about 40 percent present signs of retinopathy. This pathology afflicts younger patients with respect to senile macular degeneration, thereby presenting higher costs to the society, especially in terms of productivity. Diabetic retinopathy has been studied on anatomic-pathological bases, and the major alterations involve the coriocapillaris. The alterations consist in thickening of the basal membrane, selective loss of intramural pericytes (those surrounding the endothelial cells), development of vascular insufficiency, and passage of liquid. These alterations give rise to local edema and finally development of regional tissue hypoxia. Diabetic retinopathy can be classified in four major groups: 1) nonproliferant, 2) initial, 3) preproliferant, and 4) proliferant.

Areas of hypoxia can be evidenced by fluorangiography of the retina. In advanced diabetic retinopathy the retina shows vast areas of hypoxia and capillary nonperfusion. The neovascolarization which involves the optic nerve head and other areas is secondary to hypoxia in the areas of reduced or absent capillary perfusion. The retinal alterations progress slowly over many years. The most precise parameter to

foresee the incidence and prevalence of retinopathy in the diabetic population is the duration of diabetes.

The possibility of developing diabetes increases with age; nearly all patients with diabetes older than 20 present some signs of retinopathy. However, retinal alterations must be studied at all stages, even if the longer the duration of diabetes, the higher the risk of developing retinopathy. The diagnosis of diabetic retinopathy is based on a detailed examination of the fundus oculi with ophthalmoscopy. The fundus examination should be carried out after pupillary dilatation with tropicamide 1 percent or phenilephrine 2.5 percent.

The retinal alterations in diabetic retinopathy begin at the capillary level with thickening of the basal membrane and loss of endothelial cells and pericytes. There is an increase in blood density and reduced deformability of blood cells; these alterations lead to occlusion of the capillaries and transudation of liquids. The final stage is the simultaneous presence of edematous and haemorrhagic areas (defined as humid), alternated with ischaemic areas due to reduced perfusion (defined as dry). The damage to vision caused by diabetic retinopathy is represented by direct damage, iatrogenic damage, and damage due to secondary pathologies.

Direct damage includes the following:

●maculopathy—the exudative form represented by focal macular edema, and the ischaemic or dry form;

●cystoid macular edema (in the advanced stages);

●optic neuropathy, with loss of portions of central vision;

●retinal haemorrhage—the preretinal forms can cover large areas of the central visual field;

●central or branch venous occlusion; and

●tractional retinal detachment.

The damage caused by diabetes is associated with iatrogenic damage due to therapeutic stategies aimed at preventing long term effects of diabetic retinopathy. These include the following:

●argon laser treatment on central neovascular membranes;

●central grid with krypton laser;

●paracentral focal laser treatment;

●peripheral panphotocoagulation;

●retinal haemorrhages and cystoid macular edema secondary to panphotocoagulation;

●photodynamic treatment;

●vitreoretinal surgery;

●silicone oil; and

●surgical complications of cataract and glaucoma.

Among the damage induced by secondary pathologies are the following:

●cataracts;

●neovascular glaucoma; and

●cerebral damage which arises due to diabetes.

In the past decade there has been much progress in the management of diabetic retinopathy. The treatment of choice is laser photocoagulation. It is thus possible to control proliferative diabetic retinopathy, which can cause exudative maculopathy.

Laser photocoagulation can be carried out in the office with a slit lamp. It is a relatively painless procedure requiring two to four sessions lasting 20-30 minutes each. A total of 1200-1500 spots with diameter of 200-500 microns are placed, avoiding the optic nerve head, the macula, and principal vessels.

The neovascularization of the optic nerve head is not directly treated; however, the aim is the involution of neovessels in a variable period of three weeks to three months.

Since the principle cause of blindness in diabetic retinopathy is vitreal haemorrhage, caused mainly by neovascularization, the reduction or disappearance of new vessels in the optic nerve head and in other areas reduces the incidence of blindness.

In patients with proliferative diabetic retinopathy treated with laser photocoagulation the statistical risk of severe loss of vision is reduced by 50 percent. There are unfortunately patients who present a progression of disease, vitreal haemorrhage, and blindness even after adequate laser photocoagulation.

The majority of patients have some reduction of central vision (reading) corresponding to two lines of Snellen tables. At times this loss of vision is permanent, but generally it is temporary.

In a significant number of patients there are visual field defects, at times with lateral defects. In the majority of patients there is nocturnal vision reduction, limiting driving at night. In the last decade many microsurgery techniques have been put forward to treat vitreal haemorrhages. In diabetic retinopathy vitreal gel is important in the development of neovessels. If this gel contracts (vitreal separation) or liquefies (syneresis), the delicate neovascular net can break with consequent vitreal haemorrhage. Vitrectomy should be taken into consideration under the following conditions:

1)vitreal haemorrhage which does not resolve in 6 months;

2)tractional retinal detachment (caused by vitreous contraction) which involves the macula;

3)vitreal haemorrhage followed by retinal detachment; or

4)bilateral vitreal haemorrhage.

Vitrectomy does present significant risks, but it is the sole hope in selected cases. Visual reduction is defined as slight (5-8/10), intermediate (1-4/10), and severe (less than 1/10). An intermediate state of vision reduction is most frequently encountered. Less visual reduction is seen in nonproliferative retinopathy, whereas in the proliferative phase of disease there is severe loss of vision. Nonproliferative retinopathy causes maculopathy with retinal edema in the foveal area and consequent reduction of central vision. This is usually well diagnosed with fluorangiography. This edema and the typical yellow exudates which are frequently associated with it are caused by exudation from vessels with altered walls and/or microaneurisms. The exudates frequently form a partial or complete ring in, near, or around the macular area (circinate maculopathy). Generally it is thought that adequate

control of blood glucose and normal levels of glycosylated haemoglobin delay the onsent of retinopathy and/or reduce the progression of vascular alterations.64-66 It is noted that a state of ketoacidosis or hyperosmolarity can cause alterations in refraction. In diabetic patients corrective lenses should not be prescribed until the clinical condition is stable.

Other critical systemic diseases for the diabetic patient are: hypertension, atherosclerotic lesions of the carotid arteries, and cardiac or renal alterations.

In conclusion, diabetic retinopathy is an ocular pathology, but collaboration with the internist is appropriate in order to offer complete and effective treatment to the patient.

Degenerative Myopia

The simple definition of myopia is: a refractive error in which light rays from an infinite point are focused in a static refractive state on a plane in front of the retina. This occurs with a longer antero-posterior length of the eye and/or a higher ocular diopter power.67 Degenerative myopia is considered a true disease, with degenerative pathology of the sclera, choroid, and retina. This form is always due to an abnormal development of the antero-posterior axis of the eye with values which can exceed 30 mm. It has a progressive evolution. Of all patients afflicted with myopia, the percentage of the degenerative form is 6-8 percent and females are more frequently involved. The disease begins around three to four years of age and progresses throughout life. The progression has individual variability. The high myope has large, slightly protruding eyes, blinks frequently, and sometimes presents divergent strabismus. Visual acuity is not always perfect, but near vision is usually maintained. The progressive nature of the disease, however, can reduce visual function over time. The chorioretinal complications usually lead to a negative prognosis.68-70 Even though degenerative myopia is not strictly a disease of the older population, the progressive characteristic makes it one of the principal causes of low vision and blindness in the elderly. The etiopathogenesis of myopia has been much discussed.71 A myriad of hypotheses have been advanced; we would like to present the theory of Balacco Gabrieli, in which degenerative myopia is considered not only a refractive state but a disease which involves many genetic and neuroendocrine mechanisms.72-74 The most important anatomic-pathological condition of the eye is the excessive increase in the antero-posterior length. In the most severe forms there is a scleral elongation of the posterior pole causing the myopic stafiloma. The visual disfunction of the uncorrected or undercorrected myopic eye would influence the encephalic-hypophyseal axis, causing an endocrine alteration responsible for a weakening of the scleral collagen.75,76 The luminous stimulus which reaches the eye is transmitted to the hypothalmus and the hypophysis, and the latter, in turn, through the secretion of melatonin, interferes with gonadal func- tion.77-79 The hypothalamus, on the other hand, regulates the function of other endocrine glands through the hypophysis.80

The eye is linked to the central nervous system through two paths:81,82 1) the optical, and 2) the retinal-hypothalmic.

In the hypothesis of Balacco-Gabrieli the myopic eye, with genetic predisposition, sends an abnormal visual message to the encephalo-hypophysis axis with a consequent alteration of the secretion of some hormones, especially the steroidal hormones.83-85 This hormonal alteration influences the sclera, causing progressive weakening and elongation of the eye. There is also a parallel increase of the urinary excretion of acid mucopolysaccharides, which demonstrates collagen metabolism alteration86 The influence of the luminous stimulus on the retina is of fundamental importance; the myopic eye sends insufficient (or better, abnormal) stimuli to the encephalic-hypophyseal axis.87-92 The encephalic-hypophyseal axis reacts to the modified message with a increase of steroidal hormones and a modified secretion of neurotransmitters and neuromodulators (VIP) of the retinal neurons, causing a further increase in the growth of the eye.93-98

The myope has reduced visual acuity without optical correction by means of spectacles or contact lenses. Over the past two decades photorefractive methods have been refined in the correction of myopia.99-102 The causes of low vision and blindness in degenerative myopia have individual variability. Some complications, such as glaucoma and cataract, can be solved with medical and surgical management.103 Other complications, such as chorioretinal degeneration, can be severe and progressive, with negative prognosis. These alterations can be divided into macular and peripheral retinal alterations. Myopic maculopathy can be classified as atrophic, hemorrhagic, or exudative-haemorrhagic with a neovascular membrane. The final state is almost always dry chorioretinal degeneration. Fluorangiography, indocyanine green angiography, and optical coherence tomography are new instrumental measures which allow early diagnosis and better management methods. Treatment has involved photocoagulative argon laser therapy, but new measures such as photodynamic treatment are now being used.

The peripheral degenerations have clinical importance, as some can evolve towards retinal detachment. Laser preventive measures and routine retinal examination is of fundamental importance.104-106

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